Ghrelin—Satisfying a Hunger for the Mechanism

Ghrelin was first described in 1999 by Kojima et al. (1); it was identified as the long-awaited endogenous ligand to the GH secretagogue receptor (GHS R) and a peripheral metabolic signal informing the brain about stomach nutrient load. Ghrelin quickly became the focus of intense investigation in many laboratories and was the subject of more than 600 publications by early 2004. Because of the potential importance of ghrelin in the regulation of feeding, it was originally promoted as a target for the treatment of obesity; however, it may be more immediately useful in the treatment of wasting syndromes, driving increased food intake and GH release. Regardless, a hormone released by an empty stomach presents a novel drug development opportunity. Can blocking ghrelin suppress hunger and decrease body weight? It is well recognized that hypothalamic circuits, especially arcuate circuits, inform the brain about the energy status of the body. Although there is strong evidence supporting a hypothalamic mode of action, there is also evidence that ghrelin may work via the hindbrain. Therefore, there is still debate about the mechanism of action as well the circuitry by which ghrelin modifies feeding. The paper by Chen et al. (2) in this issue of Endocrinology is a timely report providing compelling evidence that peripheral ghrelin acts through hypothalamic neuropeptide Y (NPY)/agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neurons to stimulate feeding, hopefully ending the debate about the main site of action of ghrelin.